Figure 1

Predicted effects of amino acid substitutions on TSC1. (A) Plot of BLOSUM 62 scores for substitutions in the LOVD TSC1 mutation database. Positive values represent conservative substitutions, negative values represent non-conservative substitutions. Substitutions investigated in this study are indicated. (B) Plot of Grantham scores for substitutions in the LOVD TSC1 mutation database. The higher the Grantham score, the less conservative the substitution. Substitutions investigated in this study are indicated. (C) SIFT analysis of TSC1. Each amino acid is represented by a box. Solid green boxes represent positions that are completely tolerant (all substitutions possible); open green boxes represent positions where 1 or 2 substitutions are not tolerated. Solid red boxes represent intolerant positions (no substitutions tolerated); open red boxes represent positions where 3 or fewer substitutions are tolerated. Empty boxes represent positions where between 3 and 17 substitutions are tolerated. The positions of substitutions tested in this study are indicated in blue. (D) Comparative hydrophobicity profile of wild-type TSC1 with variants predicted by SIFT analysis to be tolerated. Hydrophobicity values were calculated for each amino acid using DNAMAN software (default parameters). Differences in the predicted hydrophobicity per amino acid were plotted. Values > 0 indicate an increase in hydrophobicity of the variant relative to wild-type; values < 0 indicate a decrease. Variants analysed as part of this study are indicated. (E). Comparative hydrophobicity profile of wild-type TSC1 with variants predicted by SIFT analysis not to be tolerated.